WO2003093233A1 - Process for the preparation of the amorphous form of atorvastatin calcium salt - Google Patents

Process for the preparation of the amorphous form of atorvastatin calcium salt Download PDF

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Publication number
WO2003093233A1
WO2003093233A1 PCT/EP2003/004313 EP0304313W WO03093233A1 WO 2003093233 A1 WO2003093233 A1 WO 2003093233A1 EP 0304313 W EP0304313 W EP 0304313W WO 03093233 A1 WO03093233 A1 WO 03093233A1
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WO
WIPO (PCT)
Prior art keywords
calcium salt
atorvastatin calcium
water
atorvastatin
organic solvent
Prior art date
Application number
PCT/EP2003/004313
Other languages
French (fr)
Inventor
Stefano Turchetta
Pietro Massardo
Angela Tuozzi
Original Assignee
Chemi S.P.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chemi S.P.A. filed Critical Chemi S.P.A.
Priority to CA002483862A priority Critical patent/CA2483862A1/en
Priority to EP03727362A priority patent/EP1509500B1/en
Priority to DE60302571T priority patent/DE60302571T2/en
Priority to AT03727362T priority patent/ATE311365T1/en
Priority to US10/512,895 priority patent/US20060128971A1/en
Priority to AU2003233064A priority patent/AU2003233064A1/en
Publication of WO2003093233A1 publication Critical patent/WO2003093233A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Definitions

  • the present invention relates to a reproducible method for preparing the amorphous form of atorvastatin calcium salt, in such a way as to be easily filtered, and with a purity superior to the initial crystalline form.
  • Atorvastatin is a well known active pharmaceutical principle widely used for the treatment of diseases caused by hypercholesterolaemia.
  • US4681893, US5273995, US6121461 , US5969156 refer to the preparation of the product both in amorphous and crystalline form. While the production of a composition with a well defined crystalline form can in many cases be advantageous from the point of view of stability and from the point of view of the dosage of the active principle in the pharmaceutical formulation, in some cases this can give rise to water solubility and bioavailability differences. This is the case with atorvastatin where the corresponding amorphous form demonstrates superior characteristics of water solubility and bioavailability than the corresponding crystalline form.
  • the known processes for producing atorvastatin in amorphous form present problems due to the poor reproducibility and/or poor workability of the product or are not suitable for scale up to industrial production.
  • WO0128999 describes the preparation of amorphous atorvastatin by precipitating the product from solutions of atorvastatin calcium salt in lower alkanols. In this case enormous quantities of alcohols are necessary to obtain the desired product.
  • atorvastatin calcium salt can be produced in amorphous form, by a method that does not present the inconveniences of the state of the art.
  • the process of the present invention comprises: a)dissolving the atorvastatin calcium salt in an organic solvent miscible with water, b) gradually adding said solution to water while stirring, c) filtering and vacuum drying the solid obtained.
  • Figure 1 shows the x-ray diffraction spectrum of the amorphous atorvastatin prepared as described in example 1.
  • the atorvastatin used as starting material can be either crystalline or amorphous.
  • the atorvastatin used in stage (a) of the process of the present invention can therefore be crystalline atorvastatin of form (I), (II) and (IV) as described in US5969156 form (III) as described in US6121461 or the amorphous form derived from the reaction described in US5273995.
  • the water miscible solvent is preferably chosen from: tetrahydrofuran, dimethylsulphoxide, dimethylacetamide, dimethylformamide, N-methylpyrrolidone, sulfolane.
  • the additional advantage of this method is that the product obtained, whose amorphous nature is confirmed by the relative x-ray diffraction spectrum, has a higher purity than the starting product.
  • the atorvastatin calcium salt is dissolved in a quantity of organic solvent between 0.5 and 20, more preferably between 1 and 10 and even more preferably between 1 and 5 n l/gram of the atorvastatin calcium salt in crystalline form.
  • the amount of water, to which the atorvastatin in organic solvent is slowly added is preferably between 5 and 100, more preferably between 10 and 50, and even more preferably between 10 and 30 ml/gram of atorvastatin calcium salt in crystalline form.
  • the temperature of the constantly stirred water is between 5 and 40°C, preferably between 10 and 30°C.
  • the water soluble organic solvent is tetrahydrofuran.
  • the mixture is stirred for a period of time between 0.5 and 5 hours, preferably between 1 .and 3 hours and even more preferably between 2 and 3 hours at a temperature of between 5 and 40°C and preferably between 10 and 30°C, after which the suspension is filtered and the solid washed with water.
  • a further advantage of this method lies in the good filterability of the solid obtained due to the addition of the organic solution to the water. Indeed the addition of water to the organic solution results in the formation of gummy masses which cannot be filtered or stirred.
  • Figure 1 shows the x-ray diffraction spectrum of the atorvastatin calcium salt in amorphous form thus obtained, a spectrum which is entirely in accordance with those already reported in the literature for such a product.
  • EXAMPLE 2 shows the x-ray diffraction spectrum of the atorvastatin calcium salt in amorphous form thus obtained, a spectrum which is entirely in accordance with those already reported in the literature for such a product.
  • a 500 ml reactor equipped with mechanical stirrer and dropping funnel is filled with 200 ml of deionized water, maintained at 22-25°C.
  • 20g of crude amorphous atorvastatin calcium salt derived from the reaction mixture of the process described in US5273995 are dissolved in 30 ml of N,N-dimethylacetamide and loaded into the dropping funnel.
  • the organic solution is then slowly dripped onto the water and a white solid is formed.
  • the mixture is stirred for about 1 hour at 22-25°C and is then cooled to 10°C and maintained at that temperature for 1 hour.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyrrole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

Process for preparing atorvastatin calcium salt in amorphous form comprising: a) dissolving the atorvastatin calcium salt in an organic solvent miscible with water, b) gradually adding said solution to water while stirring, c) filtering and vacuum drying the solid obtained. Formula.

Description

PROCESS FOR THE PREPARATION OF THE AMORPHOUS FORM OF ATORVASTATIN CALCIUM SALT.
FIELD OF THE INVENTION The present invention relates to a reproducible method for preparing the amorphous form of atorvastatin calcium salt, in such a way as to be easily filtered, and with a purity superior to the initial crystalline form. STATE OF THE ART
Atorvastatin is a well known active pharmaceutical principle widely used for the treatment of diseases caused by hypercholesterolaemia. US4681893, US5273995, US6121461 , US5969156 refer to the preparation of the product both in amorphous and crystalline form. While the production of a composition with a well defined crystalline form can in many cases be advantageous from the point of view of stability and from the point of view of the dosage of the active principle in the pharmaceutical formulation, in some cases this can give rise to water solubility and bioavailability differences. This is the case with atorvastatin where the corresponding amorphous form demonstrates superior characteristics of water solubility and bioavailability than the corresponding crystalline form. On the other hand the known processes for producing atorvastatin in amorphous form present problems due to the poor reproducibility and/or poor workability of the product or are not suitable for scale up to industrial production.
For example in US6087511 and US6274740 are described the preparation of the amorphous form of atorvastatin calcium salt starting from the crystalline form (I) by evaporating the solution of the product in organic solvents such as tetrahydrofuran or tetrahydrofuran-toluene, until a foamy solid residue is obtained. This method presents considerable drawbacks from the point of view of industrial application. In regard to the workability of the product, at the end of the preparation a fragile foam is obtained which must be broken up in the reactor and must be discharged from the reactor as a solid. WO007116 reports the production of atorvastatin in amorphous form from a solution of the product in a non-hydroxylic solvent. In this case high levels of hydrocarbon are necessary to obtain the desired product. WO0128999 describes the preparation of amorphous atorvastatin by precipitating the product from solutions of atorvastatin calcium salt in lower alkanols. In this case enormous quantities of alcohols are necessary to obtain the desired product. TECHNICAL PROBLEM
It was therefore considered necessary to provide a method for producing atorvastatin in amorphous form that was economically advantageous and at the same time industrially scalable. SUMMARY OF THE INVENTION
The applicant has unexpectedly found that atorvastatin calcium salt can be produced in amorphous form, by a method that does not present the inconveniences of the state of the art.
In particular the process of the present invention comprises: a)dissolving the atorvastatin calcium salt in an organic solvent miscible with water, b) gradually adding said solution to water while stirring, c) filtering and vacuum drying the solid obtained. DESCRIPTION OF THE FIGURE
Figure 1 shows the x-ray diffraction spectrum of the amorphous atorvastatin prepared as described in example 1.
The measurements were made at the wavelengths Kα1 and Kα2 using 5.000° for angle 2Θ and 35.000° for the final angle. In this figure, in ordinates the number of ' "' counts per second is reported, and in abscissae the values of the angle 2Θ.
DETAILED DESCRIPTION OF THE INVENTION
The atorvastatin used as starting material can be either crystalline or amorphous.
Consequently the atorvastatin used in stage (a) of the process of the present invention can therefore be crystalline atorvastatin of form (I), (II) and (IV) as described in US5969156 form (III) as described in US6121461 or the amorphous form derived from the reaction described in US5273995.
Preferably this latter type of atorvastatin is used.
The water miscible solvent is preferably chosen from: tetrahydrofuran, dimethylsulphoxide, dimethylacetamide, dimethylformamide, N-methylpyrrolidone, sulfolane. The additional advantage of this method is that the product obtained, whose amorphous nature is confirmed by the relative x-ray diffraction spectrum, has a higher purity than the starting product. Preferably the atorvastatin calcium salt is dissolved in a quantity of organic solvent between 0.5 and 20, more preferably between 1 and 10 and even more preferably between 1 and 5 n l/gram of the atorvastatin calcium salt in crystalline form. The amount of water, to which the atorvastatin in organic solvent is slowly added, is preferably between 5 and 100, more preferably between 10 and 50, and even more preferably between 10 and 30 ml/gram of atorvastatin calcium salt in crystalline form. The temperature of the constantly stirred water is between 5 and 40°C, preferably between 10 and 30°C. Preferably the water soluble organic solvent is tetrahydrofuran. As the solution of atorvastatin calcium salt in the organic solvent is dripped onto the stirred water, the formation of a solid is observed which becomes more consistent as the addition proceeds. At the end of the addition the mixture is stirred for a period of time between 0.5 and 5 hours, preferably between 1 .and 3 hours and even more preferably between 2 and 3 hours at a temperature of between 5 and 40°C and preferably between 10 and 30°C, after which the suspension is filtered and the solid washed with water.
A further advantage of this method lies in the good filterability of the solid obtained due to the addition of the organic solution to the water. Indeed the addition of water to the organic solution results in the formation of gummy masses which cannot be filtered or stirred. Some illustrative but non-limitative examples are given hereinafter of the preparation process according to the present invention. EXAMPLE 1
5 g of crude amorphous atorvastatin calcium salt derived from the reaction mixture of the process described in US5273995 are dissolved in 15 ml of THF and loaded into a dropping funnel. The funnel is placed above a 250 ml reaction flask equipped with mechanical stirrer. 100 ml of deionized water are loaded into the reactor and maintained at 22-25°C and from the dropping funnel the THF solution is added to the water, resulting in the formation of a white solid. When the addition is complete the suspension is cooled to 10°C while stirring and maintained at that temperature for 1 hour. The precipitate is then filtered off under reduced pressure and washed with 20 ml of deionized water. 13.4 g of a wet product is obtained which, after drying for 12 hours at 40°C under reduced pressure (50mm Hg) gives rise to 4.8 g of atorvastatin calcium salt in amorphous form (yield 95%), of a purity superior to that of the initial crude atorvastatin evaluated by means of TLC as comparison.
Figure 1 shows the x-ray diffraction spectrum of the atorvastatin calcium salt in amorphous form thus obtained, a spectrum which is entirely in accordance with those already reported in the literature for such a product. EXAMPLE 2
A 500 ml reactor equipped with mechanical stirrer and dropping funnel is filled with 200 ml of deionized water, maintained at 22-25°C. 20g of crude amorphous atorvastatin calcium salt derived from the reaction mixture of the process described in US5273995 are dissolved in 30 ml of N,N-dimethylacetamide and loaded into the dropping funnel. The organic solution is then slowly dripped onto the water and a white solid is formed. At the end of the addition the mixture is stirred for about 1 hour at 22-25°C and is then cooled to 10°C and maintained at that temperature for 1 hour. The solid is filtered off, washed with 50 ml of cold deionized water and dried under vacuum at 40°C for 12 hours to give 18.2g of atorvastatin calcium salt in amorphous form (yield 91 %) of a purity superior to the initial crude atorvastatin evaluated by means of TLC as comparison. EXAMPLE 3 The reaction is conducted starting from 20 g of atorvastatin calcium salt using the same conditions as in example 2, with the only difference that dimethylsulphoxide is used as the organic solvent miscible in water. After drying, 17.5 g of atorvastatin calcium salt in amorphous form are obtained (yield 87.5%) of a purity superior to the initial crude atorvastatin evaluated by means of TLC as comparison.

Claims

1. Process for preparing atorvastatin calcium salt in amorphous form comprising a) dissolving the atorvastatin calcium salt in an organic solvent miscible with water, b) gradually adding said solution to water while stirring, c) filtering and vacuum drying the solid obtained.
2. Process as claimed in claim 1 , characterised in that atorvastatin used in stage (a) is amorphous atorvastatin.
3. Process as claimed in claim 1 or 2, characterised in that the water miscible solvent is preferably chosen from the class consisting of tetrahydrofuran, dimethylsulphoxide,' dimethylacetamide, dimethylformamide, N-methylpyrrolidone, sulfolane. .
4. Process as claimed in claim 3 wherein said water miscible organic solvent is tetrahydrofuran.
5. Process as claimed in any one of claims 1-4, characterised in that in stage (a) atorvastatin calcium salt is dissolved in a quantity of water miscible organic solvent of between 0.5 and 20 ml/gram of atorvastatin calcium salt in crystalline form.
6. Process as claimed in claim 5, characterised in that said quantity of organic solvent is between 1 and 10 ml/gram of atorvastatin calcium salt in crystalline form.
7. Process .as claimed in claim 6, characterised in that said quantity of organic solvent is between 1 and 5 ml/gram of atorvastatin calcium salt in crystalline form.
8. Process as claimed in any one of claims 1-7 characterised in that in stage (a) the quantity of water, to which the solution of atorvastatin in organic solvent is slowly added, is between 5 and 100 ml/gram of atorvastatin calcium salt in crystalline form.
9. Process as claimed in claim 8, characterised in that said quantity of water is between 10 and 50 ml/gram of atorvastatin calcium salt in crystalline form.
10. Process as claimed in claim 9, characterised in that said quantity of water is between 10 and 30 ml/gram of atorvastatin calcium salt in crystalline form
11. Process as claimed in any one of claims 1-10, characterised in that the water temperature in stage (a) is between 5 and 40°C.
12. Process as claimed in claim 11 , characterised in that the said temperature is between 10 and 30°C.
13. Process as claimed in any one of claims 1-10 characterised in that when stage (a) has terminated, the mixture obtained is left under stirring at a temperature between 5 and 40°C for a period of time between 0.5 and 5 hours.
14. Process as claimed in claim 13, characterised in that when stage (a) has terminated, the mixture obtained is left under stirring at a temperature between 10 and 30°C for a time period between 1 and 3 hours.
PCT/EP2003/004313 2002-04-29 2003-04-25 Process for the preparation of the amorphous form of atorvastatin calcium salt WO2003093233A1 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
CA002483862A CA2483862A1 (en) 2002-04-29 2003-04-25 Process for the preparation of the amorphous form of atorvastatin calcium salt
EP03727362A EP1509500B1 (en) 2002-04-29 2003-04-25 Process for the preparation of the amorphous form of atorvastatin calcium salt
DE60302571T DE60302571T2 (en) 2002-04-29 2003-04-25 PROCESS FOR PREPARING THE AMORPH FORM OF ATORVASTATIN CALCIUM SALT
AT03727362T ATE311365T1 (en) 2002-04-29 2003-04-25 METHOD FOR PRODUCING THE AMORPHIC FORM OF ATORVASTATIN CALCIUM SALT
US10/512,895 US20060128971A1 (en) 2002-04-29 2003-04-25 Process for the preparation of the amorphous form of atorvastatin calcium salt
AU2003233064A AU2003233064A1 (en) 2002-04-29 2003-04-25 Process for the preparation of the amorphous form of atorvastatin calcium salt

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT2002MI000907A ITMI20020907A1 (en) 2002-04-29 2002-04-29 PREPARATION PROCESS OF THE AMORPHOUS FORM OF THE FOOTBALL ROOM OF ATORVASTATINA
ITMI2002A000907 2002-04-29

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EP (1) EP1509500B1 (en)
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AU (1) AU2003233064A1 (en)
CA (1) CA2483862A1 (en)
DE (1) DE60302571T2 (en)
ES (1) ES2253674T3 (en)
IT (1) ITMI20020907A1 (en)
WO (1) WO2003093233A1 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004089895A1 (en) * 2003-04-11 2004-10-21 Lek Pharmaceuticals D.D. Process for the preparation of amorphous calcium salt of atorvastatin
WO2006011155A1 (en) * 2004-07-26 2006-02-02 Apollo International Limited One pot process for amorphous atorvastain calcium
WO2006087404A1 (en) * 2005-02-16 2006-08-24 Ercros Industrial, S.A. Stabilised amorphous calcium atorvastatin and production method thereof
WO2008082250A1 (en) * 2007-01-02 2008-07-10 Cj Cheiljedang Corporation Improved process for the preparation of non-crystalline atorvastatin calcium

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2586561T3 (en) * 2004-07-16 2016-10-17 Lek Pharmaceuticals D.D. Atorvastatin calcium oxidative degradation products
WO2008053312A2 (en) * 2006-11-02 2008-05-08 Cadila Pharmaceuticals Limited Process for preparing amorphous atorvastatin hemi calcium salt and its intermediate
EP2075246A1 (en) 2007-12-27 2009-07-01 M. J. Institute of Research A process for preparation of amorphous form of atorvastatin hemi-calcium salt
WO2011028309A1 (en) 2009-09-04 2011-03-10 University Of Toledo PROCESSES FOR PRODUCING OPTICALLY PURE β-LACTONES FROM ALDEHYDES AND COMPOSITIONS PRODUCED THEREBY

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WO2000071116A1 (en) * 1999-05-25 2000-11-30 Ranbaxy Laboratories Limited Process for the production of amorphous atorvastatin calcium
WO2001028999A1 (en) * 1999-10-18 2001-04-26 EGIS Gyógyszergyár Rt. Process for the preparation of amorphous atorvastatin calcium
WO2001042209A1 (en) * 1999-12-10 2001-06-14 Lek Pharmaceutical And Chemical Company D.D. Process for the preparation of amorphous atorvastatin
US6274740B1 (en) * 1995-07-17 2001-08-14 Warner-Lambert Company Process for the production of amorphous [R-(R*,R*)]-2-(4-fluorophenyl)-β, δ-dihydroxy-5-(1-methylethy)-3-phenyl-4-[(phenylamino) carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1)
WO2002059087A1 (en) * 2001-01-23 2002-08-01 Lek Pharmaceutical And Chemical Company D.D. Preparation of non-crystalline atorvastatin calcium
WO2003018547A2 (en) * 2001-08-31 2003-03-06 Morepen Laboratories Ltd. An improved process for the preparation of amorphous atorvastatin calcium salt (2:1)

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ES2167587T3 (en) * 1995-07-17 2002-05-16 Warner Lambert Co CRYSTAL FORM OF THE HEMICALCIC ACID SALT (R- (R *, R *)) - 2- (4-FLUOROPHENIL) -BETA, DELTA-DIHIDROXI-5- (1-METHYL) -3-PHENYL-4 - (( PHENYLAMINE) CARBONIL) -1H-PIRROL-1-HEPTANOIC (ATORVASTATIN).
HRP960313B1 (en) * 1995-07-17 2002-08-31 Warner Lambert Co Form iii crystalline (r- (r*, r*)-2- (4-fluorophenyl) -beta-delta-hydroxy-5-(1-methylethyl) -3-phenyl-4- ((phenylamino) carbonyl -1h-pyrrole-1-heptanoic acid calcium salt (2:1)
US6087511A (en) * 1996-07-16 2000-07-11 Warner-Lambert Company Process for the production of amorphous [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl )-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid) calcium salt (2:1)

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US6274740B1 (en) * 1995-07-17 2001-08-14 Warner-Lambert Company Process for the production of amorphous [R-(R*,R*)]-2-(4-fluorophenyl)-β, δ-dihydroxy-5-(1-methylethy)-3-phenyl-4-[(phenylamino) carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1)
WO2000071116A1 (en) * 1999-05-25 2000-11-30 Ranbaxy Laboratories Limited Process for the production of amorphous atorvastatin calcium
WO2001028999A1 (en) * 1999-10-18 2001-04-26 EGIS Gyógyszergyár Rt. Process for the preparation of amorphous atorvastatin calcium
WO2001042209A1 (en) * 1999-12-10 2001-06-14 Lek Pharmaceutical And Chemical Company D.D. Process for the preparation of amorphous atorvastatin
WO2002059087A1 (en) * 2001-01-23 2002-08-01 Lek Pharmaceutical And Chemical Company D.D. Preparation of non-crystalline atorvastatin calcium
WO2003018547A2 (en) * 2001-08-31 2003-03-06 Morepen Laboratories Ltd. An improved process for the preparation of amorphous atorvastatin calcium salt (2:1)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004089895A1 (en) * 2003-04-11 2004-10-21 Lek Pharmaceuticals D.D. Process for the preparation of amorphous calcium salt of atorvastatin
EA013500B1 (en) * 2003-04-11 2010-06-30 Лек Фармасьютиклз Д.Д. Process for the preparation of amorphous calcium salt of atorvastatin
US8367848B2 (en) 2003-04-11 2013-02-05 Lek Pharmaceuticals D.D. Process for the preparation of amorphous calcium salt of atorvastatin
US8697741B2 (en) 2003-04-11 2014-04-15 Lek Pharmaceutical D.D. Process for the preparation of amorphous calcium salt of atorvastatin
WO2006011155A1 (en) * 2004-07-26 2006-02-02 Apollo International Limited One pot process for amorphous atorvastain calcium
WO2006087404A1 (en) * 2005-02-16 2006-08-24 Ercros Industrial, S.A. Stabilised amorphous calcium atorvastatin and production method thereof
ES2263370A1 (en) * 2005-02-16 2006-12-01 Ercros Industrial, S.A. Stabilised amorphous calcium atorvastatin and production method thereof
WO2008082250A1 (en) * 2007-01-02 2008-07-10 Cj Cheiljedang Corporation Improved process for the preparation of non-crystalline atorvastatin calcium

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ITMI20020907A1 (en) 2003-10-29
ATE311365T1 (en) 2005-12-15
ITMI20020907A0 (en) 2002-04-29
US20060128971A1 (en) 2006-06-15
ES2253674T3 (en) 2006-06-01
EP1509500B1 (en) 2005-11-30
DE60302571T2 (en) 2006-08-03
CA2483862A1 (en) 2003-11-13
DE60302571D1 (en) 2006-01-05
AU2003233064A1 (en) 2003-11-17
EP1509500A1 (en) 2005-03-02

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